Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2003-04-09
2004-07-06
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S418000, C564S443000, C548S215000
Reexamination Certificate
active
06759555
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel process for the preparation of combretastatins and of their derivatives.
2. Description of the Art
The term “combretastatins” or “stilbene derivatives” is understood to mean the derivatives of following general formula (I):
in which A represents a hydroxyl group or an amino group, and their pharmaceutically acceptable salts.
Mention may be made, among the salts, of the hydrochloride, acetate, phosphate or methanesulphonate. When A in the compound is an amino group, it can also be coupled to amino acids to result in amides, and their pharmaceutically acceptable salts.
The synthesis of stilbene derivatives or combretastatins, which can be in the form of a pharmaceutically acceptable salt, and the pharmaceutical compositions which comprise them are disclosed in U.S. Pat. Nos. 4,996,237, 5,525,632, 5,731,353 and 5,674,906. These patents disclose combretastatins and their metabolites and disclose their in vitro oncologic activity.
According to these patents, combretastatins are prepared from (3,4,5-trimethoxybenzyl)triphenylphosphonium salts, which are condensed with a 3-nitro- or 3-hydroxy-4-methoxybenzaldehyde (the hydroxyl group of which is protected) in the presence of sodium hydride or of lithium derivatives, and then the derivative obtained, when it is nitrated, is reduced in the presence of zinc.
The isomer with the cis configuration is subsequently prepared by the action of light or by chromatographic separation of the mixture.
SUMMARY OF THE INVENTION
The present invention provides novel processes for the preparation of combretastatins or stilbene compounds of formulae (I) and (III)
wherein A is
and
PG is a protecting group selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl, or the pharmaceutically acceptable salts thereof. In addition, the novel intermediate compound of formula III is disclosed and claimed.
DETAILED DESCRIPTION OF THE INVENTION
A first process route V0 1 for the preparation of derivatives of formula (I) for which A represents an amino group has first been discovered, which process is an improvement to the process disclosed in the abovementioned patents, which consists, after the Wittig condensation of (3,4,5-trimethoxybenzyl)triphenylphosphonium bromide or chloride and 3-nitro-4-methoxybenzaldehyde, in carrying out reduction of the nitro group with of iron, instead of the zinc as is used in the prior publications, which makes it possible to achieve an overall reaction yield, with respect to the aldehyde charged, of 60% (the yield with respect to the aldehyde charged in U.S. Pat. No. 5,525,632 is between 21% and 33%).
The first process route V0 2 consists in condensing 3,4,5-trimethoxybenzaldehyde with (4-methoxy-3-nitrobenzyl)triphenylphosphonium bromide or chloride. For both these first two processes routes V0 1 and V0 2, the reaction is carried out in the presence of a base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA (lithium dilsopropylamide), sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilazane.
This reaction is carried out in various solvents, such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will be adjusted by a person skilled in the art to the base used and to the solvent used.
This reaction, as regards the first process route V
0
2, is described in particular in the publication by K. G. Piney which appeared in Bioorg. Med. Chem., 8(2000), 2417-2425.
2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]nitrobenzene is reduced according to the improved process of the invention by the action of iron. It is advantageous to use an amount of iron in excess if complete conversion of the starting material is desired. This excess is advantageously greater than 2 equivalents per one mol of starting nitro derivative.
It has been shown that the same stage, carried out in the presence of zinc in acetic acid, a conventional solvent for reductions with zinc, does not make it possible to obtain complete reaction (in U.S. Pat. No. 5,525,632, the yield of the reduction carried out on the pure Z isomer varies between 46% and 66%) and, moreover, that the amounts of zinc used are large and consequently result in considerable industrial waste. Furthermore, the process generates a large amount of “azo” compound resulting from coupling between the amino formed and the nitroso intermediate in the reduction.
Reduction with nascent hydrogen, generated by ammonium formate in the presence of a conventional catalyst, such as palladium or platinum, leads to high isomerization of the double bond to the undesirable E isomer and to partial saturation of the double bond.
The abovementioned Piney publication describes the reduction by sodium hydrosulphite of a pure nitro Z isomer, obtained after chromatography and recrystallization, leading to an amino Z isomer with a yield of only 37%.
Hydrogenations with molecular hydrogen, catalysed by platinum or palladium, are rarely complete and result in particular in the saturation of the ethylenic double bond.
A second process has also been found which avoids the intermediate reduction stage necessary when starting from a nitro derivative. This is because it is much more economical to condense, according to a first method of carrying out this second process, a (3,4,5-trimethoxybenzyl)triphenylphosphonium bromide or chloride with 3-amino-4-methoxybenzaldehyde or, according to a second method of carrying out this second process, condensing 3,4,5-trimethoxybenzaldehyde with a (3-amino-4-methoxybenzyl)triphenyl-phosphonium salt.
This second process according to its two alternative forms requires a stage in which less in the way of CMR (Cancerogenic, Mutagenic or Reproductive) toxic products are given off in comparison with the first processes routes V0 1 and V0 2, which is a considerable advantage at the industrial level from the viewpoint of safety and production cost.
According to the second process route V0 3 for implementing the invention, the (3,4,5-trimethoxybenzyl)triphenylphosphonium salt and 3-amino-4-methoxybenzaldehyde are brought together and the reaction is carried out, preferably, in the presence of a base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA, sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilazane. Use is preferably made of sodium methoxide.
This reaction is carried out in various solvents, such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will be adjusted by a person skilled in the art to the base used and to the solvent used.
The reaction temperature will be adjusted by a person skilled in the art as to the base used. When methoxide is used, the reaction temperature is preferably between 0° C. and 10° C. After reaction, the base used is neutralized with an acid in aqueous solution, the organic phase is washed and concentrated, and the expected product is obtained after chromatographing the crude concentrate.
According to the second process route V0 4 for implementing the invention, in which the (3-amino-4-methoxybenzyl)triphenylphosphonium salt and 3,4,5-trimethoxybenzaldehyde are brought together, the reaction is preferably carried out in the presence of a base chosen in particular from potassium tert-butoxide, sodium tert-pentoxide, sodium hydride, butyllithium, LDA, sodium methoxide, potassium carbonate or alkaline derivatives of hexamethyldisilazane. Use is preferably made of sodium methoxide.
This reaction is carried out in various solvents, such as ethers (THF), polar aprotic solvents (acetonitrile, NMP, DMF, DMSO, and the like), alcohols, aromatic solvents or water, at a temperature which will be adjusted by a person skilled in the art to the base used and to the solv
Casimir Jean-Paul
Lavigne Michel
Malejonock Irina
Mutti Stephane
Aventis Pharma S.A.
Davis Brian
Martin Lawrence
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